Sexual transmission is the major mode of human immunodeficiency virus type 1 (HIV-1) infection worldwide. There is an urgent need to develop safe, topically applied microbicides that can efficiently reduce sexually transmitted infection by HIV-1. The applicant?s previous studies demonstrate that cellulose acetate phthalate (CAP), an inactive pharmaceutical excipient commonly used for the coating of enteric tablets and capsules has potent inhibitory activity against infection by HIV-1, herpesviruses (HSV), simian immunodeficiency virus (SlV), and several non-viral sexually transmitted disease (STD) pathogens, including N. gonorrhea, C. trachomatis, T vaginalis, and Haemophilus ducreyi, but has no effect on Lactobacilli, essential components of the normal vaginal flora. CAP has no significant in vitro and in vivo toxicity and has proven to be safe for human use. In addition, it is inexpensive. Thus, the applicant believes that CAP is an ideal candidate for rapid development as a microbicide applicable to prevention of sexual transmission of HIV-1 in both developing and developed countries. So far, the anti-HIV-l activity of CAP and its formulations have been evaluated using laboratory-adapted HIV-1 isolates. In order to bring CAP towards clinical application, it is critical to determine whether CAP (a) is also effective in blocking the infection of different target cells by distinct primary HIV-1 isolates, including cell-free and cell-associated viruses, and (b) inactivates the infectivity of these isolates. The specific aims of this Project are: 1) to evaluate the inhibitory activity of CAP on in vitro infection by primary HIV-1 strains with distinct genotypes and phenotypes; 2) to assess the virucidal activity of CAP and its formulations against primary HIV-1 isolates; 3) to determine the effect of CAP on in vitro cell-to-cell transmission of HIV-1; 4) to evaluate the efficacy and bio-compatibility of CAP in human genital and rectal tissue models of HIV-1 transmission; 5) to study the mechanism of action of CAP against infection by primary HIV-1 isolates. The goal of the proposed research is the rigorous and comprehensive pre-clinical evaluation of CAP and its formulations in order to expedite its transfer into human clinical trials.